Immunosuppressive Drugs - Zheng 4/14/16 Flashcards Preview

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Flashcards in Immunosuppressive Drugs - Zheng 4/14/16 Deck (16):
1

breakdown of immunity: 2 types: subdivisions

1. innate immunity

  • physical (skin, mucosa)
  • humoral (complement)
  • cellular (macrophages, NK cells)

2. adaptive immunity

  • humoral (antibodies)
  • cellular (T cells)

2

cytokines: effects on T cells

IL2: stimulates proliferation of T cells, B cells

3

some situations in which we might need/want to suppress the immune system

  • solid organ/tissue transplantation
  • bone marrow transplantation
  • autoimmune diseases

4

5 rules of transplantation therapy

1. get best ABO and HLA match possible organ donor

2. intensive induction

3. low-dose maintenance therapy (goal: combinatorial therapy using drugs with distinct mechs of action)

4. investigate each episode of transplant dysfunction (graft rejection, drug tox, infection)

5. modify tx as appropriate - withdraw drug if adverse rxn > benefit

5

induction therapy

two main groups of antibodies used:

1. depleting agents: kill activating lymphocytes

  • antithymocyte globulin
  • Muromonab-CD3 mAb

2. immune modulators

  • Daclizumab (anti-IL2R) mAb
  • Muromonab-CD3 mAb

intensifies initial immunosuppressive therapy in high-risk patients (repeat transplant patients, pediatric patients, pre-sensitized patients, AfAms) 

*also allows you to delay use of nephrotoxic calcineurin inhibitors

6

maintenance therapy

usually combinatorial therapy: diff drugs with diff mechs of action → synergistic effects and minimal toxicities

avoid steroids or build in steroid withdrawal

reduce calcineurin inhibitors and/or incorporate calcineurin inhibitor withdrawal in favor of serolimus

7

therapy for established rejection

use of agents against activated T cells 

  • high dose glucocorticoids
  • antithymocyte abs
  • Muromonab-CD3 mAb

8

calcineurin inhibitors

  • cyclosporine
  • tacrolimus (FK506) - new drug, approx 100x more potent

 

indication: prevention and tx of transplant rejection for organ transplants

  • useful for autoimmunes (rheumatoid arthritis, psoriasis)
  • typically used at maintenance doses bc of nephrotoxicity

 

9

calcineurin inhibitors:

 

mechanism of action

NFAT is a transcritpion factor that can bind to promoter of IL2 → trigger immune response

  • typically phosphorylated, hanging out in cytoplasm

when MHC/antigen-TCR recognition happens, T cell activation → increase in intracellular Ca

  • Ca binds to calmodulin → Ca-calmodulin bind to phosphatase calcineurin → de'Ps the NFAT → NFAT upregs transcription of IL2 and other infl cytokines

 

**calcineurin inhibitors (cyclosporine, tacrolimus) inhibit action of calcineurin → prevent upreg of IL2

10

calcineurin inhibitors:

 

PK

toxicity

drug interactions

pharmacokinetics

  • administered either IV or oral
  • primarily metabolized by hepatic P450s 

toxicity

  • renal tox is major adverse effect (up to 70% of pts)
  • other adverse effects: HTN, diabetes (esp in conjunction with glucocorticoids), tremor, hirsutism
  • increased risk of malignancies, infections

drug interactions

  • interacts with drugs that affect P450 enzymes 
    • avoid grapefruits/grapefruit juice
  • serolimus reduces metabolism → enhances calcineurin tox!!!
    • separate use of these two drugs by time

11

cytotoxic drugs x2

 

indications

side effects

drug ints

azathioprine : pro-drug → activated via reductive rxn with glutathione

  • used as adjunt to prevent kidney rejection, severe rheumatoid arthritis, some autoimmune indications
  • side effects: bone marrow suppression; increased risk of neoplasia and infection
  • drug interactions: metabolized by xanthine oxidase (blocked by allopurinol)

mycophenolate mofetil

  • mech of action: inhibitor of IMP DH (req for de novo purine synth) → B and T cells lack purine salvage pathways!!! → selectively suppresses lymphocyte proliferation!
  • approved for use in renal/liver/heart transplants to be used with calcineurin inhibitors and corticosteroids
  • toxicity: GI disturbance, myelosuppression, headache, HTN

12

mTOR inhibitors

  • sirolimus (Rapamycin) : bacterially produced macrolide - structurally related to tacrolimus
  • everolimus: ester-derivative of sirolimus

used in transplant patients, for some autoimmune conds, for some cancer conditions

mechanism of action: IL2 causes a signaling cascade that ultimate hits mTOR pathway → transcription and translation of stuff that leads to growth and metabolism

  • sirolimus and everolimus inhibit mTOR pathway 

 

13

mTOR inhibitors:

 

PK

toxicity

drug interactions

pharmacokinetics

  • oral admin: peaks after 1h, absorption affected by high fat diet
  • mainly metabolized by CYP3A4, transported by P-glycoprotein
  • verolimus half-life is shorter

toxicity

  • dose-dep increase in serum chol and TGs
  • not nephrotoxic in and of itself, but can decrease drug metab of calcineurin inhibitors and extend their half life → renal tox
  • other effects: anemia, leukopenia, infections

drug interactions

  • pay attn to admin with drugs that affect CYP3A4 and/or P-glycoprotein
  • pay attn to admin with calcineurin inhibitors (separate by time) to avoid renal tox

14

biologics (antibodies)

can interrupt MHC/antigen-TCR interaction

can interrupt IL2-IL2R interation

very specific!

 

1. antilymphocyte/antithymocyte antibodies

  • act mainly on circulating lymphocytes, also can deplete thymus-dep lymphocytes when adminstered continuously
  • used for induction therapy in organ/bone marrow transplant

2. Daclizumab antibody

  • specific for alpha subunit (CD25) of IL2R on activated T cells
    • treats acute rejection in renal transplant by acting as competitive antagonism of IL2-induced T cell prolif
  • side effects: mostly immunosuppression

3. Muromonab-CD3 antibody

  • causes destruction of CD3-bearing T cells
  • used to prevent rejection of liver/kidney/heart transplants and knock out T cells prior to bone marrow transplant
  • adverse effects: "cytokine release syndrome" → engagement of TCR leads to cytokine storm
    • admin glucocorticoids before Muromonab-CD3
  • potential acute hypersensitivity
  • increased infection

15

glucocorticoids

natural and synthetic steroid hormones

glucose+cortex+steroid

 

mech of action: binding of steroid to GR leads to 2 GR monomer forming a GR dimer → translocation into nucleus, binding to GRE → inhibit expression of cytokine genes (IL1, IL2, IL6, INF, TNFalpha) → inhibit T cell prolif, T cell dependent immunity

 

therapeutic use: organ transplant rejection, autoimmune diseases, allergic rxns, leukemia/hematopoeitic malignancies, shock, adrenocortical dysfx

 

adverse effects:

  • growth retardation (kids), muscle wasting, osteoporosis/bone loss
  • obesity, hyperglycemia, HTN
  • skin ulcers, increased infection

16

summary of action

preventing T cell activation

  • calcineurin inhibitors: inhibit NFAT-dep IL2 production
  • antibodies (antithymocyte, Muramonab): bind to TCRs and inhibits T cell activation activation process
  • glucocorticoids: bind to receptor and prevent IL2 transcription

preventing action of IL2

  • mTOR inhibitors: prevent T cell proliferation and protein synth
  • cytotoxic agents: target purine synth pathway; kill DNA/RNA synth
  • antibodies (antithymocyte, Daclizumab): recog IL receptor
  • glucocorticoids: prevent active prolif of immune cells